PROJECT SUMMARY/ABSTRACT Renal cell carcinoma (RCC) is a lethal disease whose incidence is on the rise. It is categorized into various subtypes, with clear cell RCC (ccRCC) representing about 85% of all RCC tumors. Current targeted molecular strategies, including tyrosine kinase inhibitors (TKIs), have resulted in a doubling of progression-free survival and significant gains in overall survival in ccRCC patients. Despite the therapeutic progress, complete and durable responses have been noted in only a few cases. The landscape of therapeutic approaches for advanced RCC has expanded rapidly in recent years as a result of significant progress in the development of immunotherapeutic drugs. The combination of VEGFR-targeting and immunotherapies has shown significant clinical promise and opened the possibility of a cure for this lethal disease. However, such therapies have also conferred additional toxicities ranging from moderate to adverse, requiring dose interruptions or reductions, thereby limiting the efficacy. We have developed novel bi-specific anti-CD70-VEGF trap fusion antibodies (FA) for dual targeting of CD27/CD70 and VEGFR pathways, critical for ccRCC development and progression. This antibody does simultaneously bind CD70, a ligand, specifically expressed in ccRCC, and neutralize VEGF. It is expected that intra-tumoral depletion of VEGF by anti-CD70-VEGF trap FA will overcome side-effects arising from off-target VEGF inhibition seen with systemic anti-VEGF approaches. The proposed studies will test the hypothesis that novel bi-specific anti-CD70-VEGF trap FA have two major advantages over existing VEGF neutralizing agents. By targeting the VEGF Trap to tumors, it will (i) achieve higher intra-tumoral concentrations of the VEGF Trap; and (ii) limit side-effects arising from off-target VEGF inhibition seen with systemic anti- VEGF approaches. To test our hypothesis and to validate the therapeutic value of anti-CD70-VEGF Trap FA, we propose the following Specific Aims: (1) Biochemical, biological and pharmacological characterization of newly developed anti-CD70-VEGF trap fusion antibodies, and (2) To evaluate the anti-tumor efficacy of anti- CD70-VEGF trap FA using direct human-to-mouse xenograft model of RCC.